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Dora Servidio
INTRODUCTION
The cyclosporine (CsA)-induced gingival overgrowth (GO) is a widely
documented side effect (Montebugnoli et al. 1996, Seymour et al. 2000).
Among the methods used to treat this clinical manifestation, the nonsurgical periodontal treatment associated with plaque control provided
controversial results (McGaw et al. 1987, Thomason et al.1993, Thomason
et al. 1995, Thomason et al. 1996, Somacarrera et al.1994, King et al. 1993,
Kantarci et al. 1999, Pernu et al.1992, Ellis et al. 1999, Daley et al 1991,
Stone et al 1991, Montebugnoli et al. 2000, Seymour et al.1987,
Montebugnoli et al. 1996, Hefti et al 1994, Schultz et al. 1990, Wondimu et
al 1993).
Interesting results have been obtained using metronidazole systemically.
(Wong et al. 1994, Cecchin et al. 1997); this drug, however, interferes with
the cyclosporine metabolism, thus contra-indicating the simultaneous
administration of the two molecules.
At present metronidazole is also available as mucoadhesive gel, which
allows to reach appropriate local concentrations without the above
mentioned systemic side effects.
The aim of this research is to evaluate the efficacy of locally-delivered
metronidazole used in association with the therapy of GO in heart
transplant patients treated with cyclosporine.
CHAPTER 1
1.1 Cyclosporine-induced gingival overgrowth
Cyclosporine is a cyclical hydrophobic endecaptide which derives from the
metabolic products of two species of fungi: the Trichoderma polysporum
and the Cylindrocarpon lucidum. The antimicrobial activity of the
cyclosporine is extremely weak but, as it had been shown since the first
studies, the compound had a remarkable inhibitory effect on the
lymphocytic proliferation (Borel et al. 1976). Since the discovery of its
immunosuppressive
properties
several
studies
have
shown
that
1.2 CYCLOSPORINE A
1.2.1 Pharmacokinetics
Cyclosporine can be taken orally, intramuscularly or intravenously. After
oral administration the drug is absorbed by the gastrointestinal tract in
quantities which may vary according to the patient.
The haematic peak is reached after 3-4 hours after the administration and
its half-life lasts approximately 17-40 hours (Beveridge et al. 1981).
Cyclosporine is totally hepatically metabolized by the enzymatic system
P450 mono-oxygenase (Maurer 1985). The metabolism entails the Ndemethylation, the hydroxylation
1.2.2 Pharmacodynamics
Cyclosporine inhibits many of the processes involved in the immune
response given by the T lymphocytes; in particular, a concentration of
10/20 ng/ml inhibits the synthesis of interleukin-2 and this inhibition
limits the clonal amplification of the cytotoxic T lymphocytes. At even
higher concentrations (approx. A 100 ng/ml) the drug can inhibit the
response of the cytotoxic T lymphocytes to the interleukin-2. The
mechanism through which this effect occurs is not clear yet but it is
believed that the cyclosporine causes a block as regards receptors for the
interleukin-2 located on the T lymphocytes. On the contrary, the drug does
not seem to have a significant selective action against the T lymphocytes
(Hess et al. 1982). In this way the cyclosporine seems to have a selective
action against T lymphocytes: the T suppressor lymphocytes do not
undergo any effect, while the cytotoxic T lymphocytes and the T helper are
sensitive to the drug.
Such action selectivity might be due to the capacity of the cyclosporine to
bind to these cells in a specific way (Hess & Colombani 1987) in order to
be introduced inside the structure of the cell. At this level the drug binds to
numerous proteins, particularly to the calmodulin and the cyclophilin. The
former is involved in activating the T lymphocytes, while the function of
the latter is still unknown. The bond between cyclosporine and these
proteins is calcium-dependant (Colombani et al. 1985). The resistance or
sensitivity of the T lymphocytes towards the cyclosporine may depend on
the different intracellular concentration of such proteins (Hess &
Colombani 1987).
5
with
therapy
interruption
(Laupacis
et
al.
1981);
(Vanrenterghem
et
al.
1985);
neurotoxicity
whose
CHAPTER 2
2.1 Role of antibiotics in periodontology
At present there is no unanimous opinion concerning antibiotics efficacy in
the treatment of denstruens periodontal disease; very often chemiotherapics
are used when the response to conventional mechanical therapy is
inadequate and after periodontal surgery. The choice of a chemiotherapic,
as well as its posology and duration of assumption had been lately based
only on an empirical criterion, i.e. the clinical evaluation (Ellen et al 1996).
The first antibiotics chosen to treat the high-grade periodontitis were at first
the penicilline, then the tetracyclines, thanks to their broad spectrum of
antibacterial action and their remarkable tropism towards the crevicular
fluid. More recently new information have been acquired about the
bacterial specificity in certain forms of periodontitis (Loesche
1979,
treatments
periodontitis
associated
with
Actinobacillus
10
12
CHAPTER 3
3.1 Metronidazole
Metronidazole is the result of an efficient tricomonicidal research done by
French researches in the 50s (Scully et al. 1988).
In 1962 Schinn observed that the administration of the drug to patients
affected by Trichimonas vaginalis infection and ulcerative gingivitis could
solve both pathologies.
After that Davies et al.(1964) realized that metronidazole was efficient
against the infections sustained by the spirochete and in the early 70s the
bactericidal power of the drug against the anaerobic bacteria was confirmed
(Tally et al. 1972).
More recent studies indicate a large use of the drug particularly in nonspecific vaginal infections and in the ones supported by a anaerobes and
parasites (Scully et al. 1988, Smilack et al. 1991, Rosenblatt et al 1987,
McEvoy et al. 1991, Finegold et al. 1990).
The use of metronidazole has been recently introduced in periodontology,
particularly in case of deep pockets or infections sustained by anaerobes
which do not respond to conventional therapy.
13
simultaneous food intake (McEvoy 1991, Bergen et al. 1984), which does
not influence the drug bioavailability, though.
The passage of the metronidazole inside the cells occurs through simple
diffusion: in this way the intercellular concentration rapidly approaches the
extracellular one.
The half-life of the unaltered metronidazole is about 7 hours and a half
and this half-life can, however, be altered in patients affected by liver
failure, though it remains unchanged in patients suffering from renal
failure.
The antibiotic is metabolized in the liver and mainly eliminated through
urines and feces. (Plaissance et al. 1988, Lau et al. 1987).
Thanks to its low molecular weight it reaches all tissues and fluids of the
body, including the cerebrospinal fluid, the saliva and the crevicular fluid
(Giedrys-Leeper et al.1985, Bergen et al. 1984, Lippincott 1990, Goodman
and Gilman 1990, Amon et al 1978). The concentration of metronidazole in
the creviculare fluid depends on the dose and the number of
administrations; normally the seric concentration of the drug and the
crevicular concentration are equivalent, however, Britt and Pohlod have
demonstrated that the crevicular concentration is half the seric one.
14
15
16
17
CHAPTER 4
4.1 Pharmacological properties of Elyzol 25%
4.2 Preparations
Local use of antibiotics in periodontal treatment has attracted wide interest.
The drug has been applied directly into the periodontal pockets either by a
non-degradable or a degradable carrier.
However, a non degradable carrier is less acceptable for clinical use,
because it has to be removed, after release of the active agent.
A metronidazole 25% dental gel (Elyzol ), which will vanish from the
pockets has been manufactured and developed by CABON s.p.a.
The gel consist of a semi-solid suspension of metronidazole benzoate in a
mixture of glyceryl mono-oleate (GMO) and triglyceride (sesame oil).
It will flow freely when applied to the pockets. In contact with the gingival
crevicular fluid (GCF) highly viscous liquid crystals are spontaneously
formed in the gel.
This prevents the gel from being easily expelled from the pockets. The
sparingly soluble metronidazole benzoate is released by break down of the
gel matrix (by lipases) and by diffusion of dissolved metronidazole
benzoate.
Metronidazole benzoate is subsequently hydrolyses into metronidazole by
esterases that are present in the GCF.
The free metronidazole may be absorbed directly from the pockets or be
discharged and then absorbed from the gastro-intestinal tract.
The time to reach peak plasma concentration varies from 2 to 8 h, the
concentration at 48 h is very low. Metronidazole can found in plasma
18
some
anaerobic
bacteria,
such
as
Actinobacillus
19
Sesame oil
71mg
20
4.6 Incompatibility.
No cases of chemical-physical incompatibility with other substances are
known.
4.7 Term.
36 months. The use-by date indicated on the packet refers to the intact, well
preserved product.
21
SPERIMENTAL PART
5.1 Material and method
A prospectic intra-subject double-blind longitudinal study was performed
with placebo, as regards the effects on periodontal area of metronidazole
associated with detartrasis. 6 patients (5 male, 1 female) aged between 14
and 67 (average age 45.3+20.5) who had undergone a heart transplant in a
period ranging from 22 to 77 months (average time 56.5 + 25.9) were
studied.
All patients were chosen at random in the group of patients with enhanced
gingival volume and with hyperplastic index (HI) >30 (RESPONDERS).
The evaluation of this index had been used in a previous study
(Montebugnoli et al. 1996, Seymour at al. 1991).
In order to define the hyperplastic index, full-arches alginate impressions
were taken; the study samples of the 12 front elements were divided into 10
vestibular units and 10 lingual units (fig. 1). The hyperplastic index is
formed by two components: vertical (McGaw et al. 1987) and horizontal
(Seymour et al. 1985). The vertical component measures the increase of
gingival volume in apico-coronal sense in each gingival unit and it is
graduated in 4 points; the horizontal component measures the thickening
both in vestibular and in lingual direction of each gingival unit according to
3 points.
The maximum score which can be obtained by adding the two components
and all the 20 gingival units is 100 and the HI has been expressed as a
percentage on an arbitrary basis (Fig. 10).
Each subject has undergone two kinds of treatments: 1) metronidazole +
detartrasis and 2) placebo + detartrasis. The two front (upper and lower)
sextants were divided into four hemi-sextants: upper right and upper left
22
and lower right and lower left. Each treatment was performed in two
contralateral hemi-sextants (es: upper right and lower left, upper left and
lower right) and a balanced random pre-programmed list assigned each
patient a hemi-sextants and each kind of treatment (detartrasis +
metronidazole or detartrasis + placebo).
At first all patients underwent a detartrasis performed by same operator on
both upper and lower sextants; at the end of the session ELYZOL 25%
dental gel or placebo substance was applied for each patient on the gingival
sulci with a syringe originally designed by CABON in the hemi-sextants
assigned by the random list.
The pockets were filled until gel could be seen at the gingival margin.
The same gels were applied by the same operator and in the same hemisextants 7 days after the first application, as proposed by Klinge et al.
(1992).
Any gel above the gingival margin and overflow from the applicator was
carefully collected and transferred to a plastic container.
After this procedere, the patiens were asked to spit in the container to
remove any further excess gel from the oral cavity.
The total amount of metronidazole used during applications varied from 72
to 256 mg. Between 35 and 153 mg of metronidazole was collected after
application resulting in an actual dose of metronidazole of 29-103 mg per
patient.
The average actual dose of metronidazole per tooth varied between 2 and 5
mg.
The peak plasma concentration (c max)after gel administration ranges from
223 to 1303 ng/ml.
After each application each patient was warned not to drink and eat for at
least two hours.
23
The patients were recalled 1,2,3,4 months after the second application and
an hour before each detartrasis session each patient received
2 g of
24
analysis of the
25
5.3 Results
Fig. 1 shows the time profile of the periodontal probing expressed in mm
(average + DS) in the two groups of dental elements (one treated with
detartrasis + metronidazole
belonging to the 6 patients who completed the study after 2 months. Table 1
refers to the relevant statistical analysis of the differences.
Significant F values were detected with reference to the patient variable
(the variability of periodontal probings is wide within each group) and to
the moment variable (the values of the periodontal values after 1 month
and after 2 months are significantly inferior to the basal ones; no significant
difference exists between the values detected after the 1 month and the
ones detected after the 2 month).
Non-significant F values were detected as regards the treatment variable
and the treatment x moment interaction (no significant difference exists
between the two groups as regards the decrease of periodontal probing and
between basline condition after 1 month condition).
Similar results were assessed by the statistical analysis relevant to the
variation of plaque index in the two groups of elements in the same 6
patients analyzed after two months (fig. 2 and table 2).
Different results were recorded as regards the evaluation of gingival index
(Fig. 3, Table 3). Significant F values were detected not only for the
patients and moment variables but also for the treatment X moment
variable (the decrease of values concerning periodontal index between
baseline conditions and after 1 month conditions is significantly higher in
the elements treated with detartrasis + metronidazole compared to the
elements treated with detartrasis + placebo).
Fig. 4 and Table 4 show the percentage of elements with positive bleeding
index in the two treatment groups. Statistically significant values were
26
detected after one month with respect to the baseline values; no significant
difference exists between the values recorded after 1 month and the one
recorded after 2 month. Moreover, no significant difference was detected
between the two treatment groups.
Fig. 5 shows the time profile of the periodontal probing in the two groups
of dental elements of the 4 patients who completed the study after 4
months (two out of the 6 patients had to abandon the study due to heart
complications). Table 5 makes reference to the statistical analysis of the
differences.
Once again, significant F values were recorded as regards the patient and
moment variables, while, with respect to the analysis performed on 6
patients after 2 months, a significant value appears to be also for the
treatment x moment interaction (after 4 months,
27
5.4 Discussion
In the course of GO treatment the most used procedures make reference to
the periodontal non-surgical therapy (scaling e root planing) associated
with plaque control and aiming to reduce the gingival inflammation
(Somacarrera et al. 1994, Kantarci et al 1999).
The results of our study are in accordance with Somacarrera and Kantarcis
ones: after one month from periodontal treatment the gingival volume has
already decreased significantly together with all the parameters connected
with the inflammation. The gingival conditions reached after the first
month have been unaltered for another month in the group with 6 patients
studied for 2 months and for at least other 2 months in the group of 4
patients followed for 4 months.
These results highlight that the gingival inflammation plays an important
role in the gingival overgrowth which occurs during therapy with
cyclosporine and probably enters the mechanism of pathogenesis of this
pathology, as proposed by some authors (Montebugnoli et al. 2000,
McGaw et al. 1987, Thomason etal.1993, Thomason et al. 1995,
Thomason et al. 1996, Ellis et al1999, Kantarci et al. 1999, Pernu et al.
1992, Daley et al.1991, Stone et al. 1991, Somacarrera et al. 1994, King et
al. 1993). What is, however, underlined by the present study is that the
decrease of the inflammation parameter significantly influences the grade
of gingival volume.
In addition to the non-surgical periodontal therapy procedures, the use of
metronidazole has been as well introduced among the strategies set in the
last years to control this parameter in the GO therapy; Wong et al (1994)
and Cecchin et al. (1997) showed that metronidazole assumed systemically
(400 mg/die x 7 days in the first study and 750 mg/3die x 14 days in the
second study) is efficient as regard the control of cyclolsporineinduced GO,
28
thus underlining once more that the reduction of the inflammation through
the antimicrobial action of the drug plays an important role in controlling
the gingival volume.
However, systemically taken metronidazole has an unpleasant side effect: it
inhibits the hepatic enzyme P-450, which is essential for the metabolism of
cyclosporine. Therefore, the attendant assumption of metronidazole and
cyclosporine might cause the increase of the plasmatic concentrations of
the latter, thus causing big problems connected with CsAs side effects.
In recent years antibiotic has been available in dental gel form, thus
allowing to reach adequate local concentrations without the above
mentioned systemic effects.
The efficacy of metronidazole applied locally in patients affected by
periodontitis has often turned out to be contradictory.
Stelzel and Flores de Jacoby (1996,1997) showed that metronidazole alone
does not produce higher results compared to scaling; these data are
confirmed by other studies (Klinge et al.1992, Pedrazzoli et al.1992,
Ainamo et al.1992).
But other authors highlighted that administration of metronidazole
associated with detartrasis gives better results compared to detartrasis
alone.
Noyan et al.(1997) showed that scaling and root planing associated with the
systemic assumption of metronidazole or the topical application of gel are
more efficient than only scaling or than the gel application alone in
determining a significant clinical and microbiological improvement after
42 days from the treatment. These results have been confirmed also by
other authors (Radvar et al. 1996, Hitzig et al. 1994, Loesche et al. 1984,
Loesche et al. 1991, Korman et al. 1989, Van Winkelhoff et al. 1989, Van
Winkelhoff et al. 1992, Pavicic et al.1994, Berglundh et al 1998).
29
attack.
Literature reports that other studies show a higher efficacy in the long term
than other chemiotherapics, different from metronidazole and clorexidine,
with respect to the detartrasis (Killoy et al. 1995a, Killoy et al.1996,
Stabholtz et al. 1991).
In conclusion, the results of the present study show that the reduction of
gingival inflammation reduces significantly after one month already the
extent of gingival overgrowth in patients who underwent a therapy with
cyclosporine.
Similar results have been obtained through treatment of patients with
detartrasis or with detartrasis associated with application of metronidazole
gel. After both treatments the gingival volume remains unaltered for at least
3 months.
After 4 months, however, it seems that the treatments with metronidazole
associated with detartrasis are more efficient in controlling GO compared
to the treatment with only detartrasis.
31
TABLES
32
Basal
3.87
1.5
NS
Detartrasis+placebo 3.82
1.6
Treatment
Patients
Moments
Treatment x moment
1 month
P<.01 3.21
1.1
NS
P<.01 3.35
1.2
F
1.5
14.1
15.9
1.7
NS
2 months
3.381.1
NS
NS
3.55 1.1
P
NS
P<.01
P<.01
NS
33
Basal
.62 .
70
NS
Detartrasis+placebo .66 .
71
Treatment
Patients
Moments
Treatment x moment
1 month
P<.05 .51 .73
NS
.43 .
67
P<.05
F
.8
6.9
5.3
.3
NS
2 momths
.52.74
NS
NS
.50 .71
P
NS
P<.01
P<.05
NS
34
6 patients
Detartrasis+elyzol
Basal
1.65 .
50
NS
Detartrasis+placebo 1.55 .
51
Treatment
Patients
Moment
Treatment x moment
1 month
P<.01 .83 .73
P<.01
P<.05
1.01 .
67
F
.4
6.9
106.9
4.4
NS
2 months
1.03.74
NS
NS
1.09 .71
P
NS
P<.01
P<.01
P<.05
35
6 patients
Detartrasis+elyzol
Detartrasis+placebo
Basal
64%
NS
53%
1 month
P<.01
18%
NS
P<.01
18%
NS
NS
2 months
18%
NS
24%
36
Basal
Detartrasis
+ elyzol
3.96
P<.01
1.6
NS
3.97
P<.01
1.7
Detartrasis
+ placebo
Treatment
Patients
Moment
Treatment x moment
1
month
3.20
1.1
NS
3.39
1.2
NS
NS
2
month
s
3.23
1.1
NS
3.44
1.2
F
2.06
35.9
9.9
5.5
NS
NS
3
month
s
3.16
1.1
NS
3.42
1.2
NS
NS
4
month
s
3.32
1.2
P<.05
3.65*
1.3
P
NS
P<.01
P<.01
P<.05
37
Detartrasis
+ placebo
Basal
.75
P<.05
.76
NS
.79
P<.05
.74
Treatment
Patients
Moment
Treatment x moment
1
month
.60
.81
NS
.52
.74
NS
NS
2
month
s
.60
.73
NS
.44
.68
F
.7
9.7
3.6
0.6
NS
NS
3
month
s
.56
.76
NS
.44
.74
4
months
NS
NS
.52
.65
NS
.50
.71
P
NS
P<.01
P<.05
NS
38
Basal
Detartrasis
+ elyzol
1.70
P<.01
.51
NS
1.60
P<.01
.64
Detartrasis
+ placebo
Treatment
Patients
Moment
Treatment x moment
1
month
.70
.61
NS
.89
.74
NS
NS
2
month
s
.83
.53
NS
.92
.60
F
.8
10.9
73.4
0.5
NS
NS
3
month
s
.75
.60
NS
.83
.64
NS
NS
4
month
s
.79
.65
NS
.77
.71
P
NS
P<.01
P<.01
NS
39
Basal
Detartrasis
+ elyzol
69% P<.01
10%
NS
NS
Detartrasis
+ placebo
56%
1
month
P<.01
10%
2
month
s
NS
4%
3
month
s
NS
NS
NS
10%
10%
4
month
s
NS
NS
NS
10%
10%
NS
NS
15%
40
Patients
1
2
3
4
5
6
Basal
64
42
56
59
84
49
1 month
58
30
49
43
64
45
2 months
57
30
53
44
71
53
3 months
4 months
37
47
46
62
32
42
52
71
41
FIGURES
42
mm
5
4,5
**
4
3,5
3
**
2,5
2
0
Basal
Metronidazole+ Detartrasis
1 Month
2 Months
Placebo + Detartrasis
43
1
0,8
0,6
0,4
0,2
0
0
Basal
1Month
Metronidazole+detartrasis
2Month
s
Placebo+detartrasis
44
2
1,5
**
**
0,5
0
0
Basal
1 Month
Metronidazole + Detartrasis
2 Months
Placebo + Detartrasis
45
70
60
50
ns
**
40
30
20
10
0
BASALE
1 MESE
Metronidazole +detartrasis
2 MESE
Placebo+detartrasis
46
**
**
2
1
0
BASAL
1 Month
Metronidazole + detartrasis
2 Months
3 Months
4 Months
Placebo + detartrasis
47
1,2
1
0,8
0,6
0,4
0,2
0
BASAL
1
2
E
moME
MESE
Metronidazole+detartrasisI
SE
3
4
MESE
MESE
Placebo+detartrasis
48
**
1,5
1
**
0,5
0
BASAL
1month
Metronidazole+placebo
2months
3months
4months
Placebo+detartrasis
49
80
70
60
50
**
40
30
20
10
0
BASALE
BASAL
1 MESE
Metronidazole+detartrasis
2 MESE
3 MESE
4 MESE
Placebo+detartrasis
50
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51
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file http://etd.adm.unipi.it/theses/available/etd-05092006-100608/unrestricted/dottorato.doc.
62
SUMMARY
INTRODUCTION ..pag 2
CHAPTER 1
1.1 Cyclosporine-induced gingival overgrowth pag 3
1.2 Cyclosporine A
1.2.1 Pharmacokinetics .pag 4
1.2.2 Pharmacodinamics ...pag 5
1.2.3 Side effects ...pag 7
CHAPTER 2
2.1 Role of antibiotics in periodontology pag 8
2.2 Assumption of the antibiotic therapy .pag 9
2.3 Systemic vs topic antibiotic therapy ..pag 11
CHAPTER 3
3.1 Metronidazole pag 13
3.2 Chemistry and pharmacokinetics ...pag 14
3.3 Mechanism of action ..pag 15
3.4 Antimicrobial spectrum .pag 16
3.5 Side effects .pag 17
CHAPTER 4
4.1 Pharmacological properties of Elyzol 25% pag 18
4.2 Preparations pag 18
63
SPERIMENTAL PART
CHAPTER 5
5.1 Material and method .pag 22
5.2 Statistical evaluation .pag 25
5.3 Results ...pag 26
5.4 Discussion .pag 28
TABLES ..pag 32
FIGURES pag 42
REFERENCES pag 51
64
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